Project Summary/Abstract: Molecular and Biochemical Etiology Program (MBEP) The overall goal of the Molecular and Biochemical Etioogy Program (MBEP) is to discover and validate novel mechanisms of cancer initiation and progression that could lead to new biomarkers and therapeutic targets, with an emphasis on breast, prostate, and ovarian cancers. The members of this program focus on the discovery of alterations in molecular mechanisms that maintain genome stability, intracellular signaling mechanisms, and tumor cell-microenvironment interactions, as well as the development and application of in vitro cell-based and whole animal-based models to validate cancer mechanisms, biomarkers, and targets. The MBEP has 26 members from seven departments across the University of Nebraska with multidisciplinary interests in DNA damage/repair processes, signaling mechanisms and cancer models. Eleven new members have been recruited to MBEP over the current funding period. The program membership has technical strengths in yeast genetics, X-ray crystallography, genomics, epigenetics, proteomics, molecular/biochemical approaches to signaling, imaging, stem cell biology, xenograft models, and sophisticated gene knockout/transgenic model development and application. The research interests of the program faculty are organized around three themes: Genome Instability and Cancer, Signaling Mechanisms in Cancer, and Cellular Basis of Cancer. Investigators within the Genome Instability and Cancer theme are focused on studies of genome replication, DNA damage responses and repair, and identification of new genomic alterations that drive hereditary or sporadic cancer. Investigators within the Signaling Mechanisms in Cancer theme focus on the alterations in intracellular signaling and tumor cell-microenvironment interactions involved in the cancer initiation, progression, and metastasis. Members within the Cellular Basis of Cancer theme focus on developing and applying cellular and animal models to understand the cellular origins of cancer, with an emphasis on stem cell biology and to validate mechanisms, biomarkers, and targets identified in other themes. The Co-Directors leverage their expertise to enhance inter- and intra-programmatic collaboration through the enhancement of shared resources, evaluation and funding of pilot projects supporting the MBEP mission, involvement in faculty recruitment efforts across the campus, the invitation of prominent scientists to speak at Cancer Center Grand Rounds and seminars, and the organization of regular programmatic meetings. These activities have led to a strongly collaborative group as demonstrated by inter- and intra-programmatic publications and grants, and the increased focus on clinical translation of discoveries from MBEP investigators. During the previous funding period, 386 manuscripts were published by MBEP investigators, of which 26.7% were intra-programmatic, 21.5% were inter-programmatic publications, and 11.7% are both intra- and inter- programmatic. The MBEP has $5.76M in total peer-reviewed funding ($4.01M direct) of which 58% is from the National Cancer Institute.